Pharmacological methods
Dinoprostone
There are two major synthetic prostaglandins utilized for cervical ripening and labour induction, dinoprostone (PGE2) and misoprostol (PGEi). Dinoprostone is most commonly used for cervical ripening in women with an unfavourable cervix where it is shown to improve the Bishop score, and reduce the need for oxytocin augmentation and caesarean section compared to placebo.
However, the relative risk of hyperstimulation is greater compared to placebo (39). Dinoprostone can be administered as a gel, a slow- release drug-eluting tampon (Cervidil or Propess), or tablet. Tablets and gels are seen to be equally effective when given in the vagina. Intracervical dinoprostone results in a slower induction, likely because of the highly absorptive properties of the vaginal mucosa. Dinoprostone has been utilized orally but has a high rate of gastrointestinal side effects.Misoprostol
Misoprostol, originally intended to treat gastric ulcers (currently its only indicated use from the Food and Drug Administration in the United States), may be used for both cervical ripening and labour induction when used at low doses. It is both cheaper and more heat stable at room temperatures than dinoprostone, making it an attractive option for both low- and high-resource settings. Misoprostol may be used orally, buccally or sublingually, vaginally, or rectally. Some countries have a 25 mcg oral tablet or vaginal pessary available. However, the most commonly available tablets are 200 mcg which require tablets to be cut into very small and typically inaccurate doses. A more accurate dosing regimen is achieved when a 200 mcg tablet is dissolved in 200 mL of water and divided accordingly. This solution is stable at room temperature for approximately 24 hours and should be stirred prior to each use.
Vaginal misoprostol is most typically used for cervical ripening and when given as 25 mcg every 4 hours leads to equivalent outcomes to vaginal dinoprostone.
Oral misoprostol solution when dosed as 20 mcg every 2 hours is as effective as vaginal dinoprostone for cervical ripening and has a lower caesarean section rate. Titrated oral misoprostol solution has also been used during induced labour for augmentation (in lieu of oxytocin). Women are given 5-20 mcg orally every 1-2 hours with the goal of maintaining a minimum of three contractions every 10 minutes. This regimen is commonly used following induction with oral misoprostol solution, and appears to be as effective and safe as oxytocin (40).Oxytocin
Synthetic oxytocin, often referred to as ‘pitocin’, is identical to the endogenous form produced in the hypothalamus and secreted by the posterior pituitary. Oxytocin is given intravenously, it cannot be given orally; it becomes inactive after breakdown in the gastrointestinal tract. Typically, oxytocin is used for labour induction or augmentation although a few studies document its use for cervical ripening at low continuous dosing. A Cochrane systematic review found that oxytocin used alone for cervical ripening reduced the rate of vaginal births within 24 hours compared to vaginal dinoprostone (21% vs 70%) and led to a 9% higher use of epidural for pain relief (41). The exception to this correlation is the use of only oxytocin in the setting of term, prelabour, spontaneous rupture of membranes where it is seen to be equally effective as prostaglandins followed by oxytocin (42).
Oxytocin binds to receptors in the myometrium which are found after 20 weeks’ gestation and increasing over the course of pregnancy as well as during the course of spontaneous labour (7). Theoretically, therefore, oxytocin should be most effective when used to augment existing labour. Its most common uses are for labour augmentation following induction or with ARM following cervical priming. The only alternative for this indication is oral misoprostol, as explained previously. When oxytocin is used in combination with ARM, it is as effective at achieving vaginal delivery as using dinoprostone but with less maternal satisfaction (41).
There are no differences in hyperstimulation rates when comparing oxytocin and prostaglandin use (41).Mifepristone
Mifepristone is a progesterone antagonist that sensitizes the uterus to prostaglandins. When used alone, it results in labour in only 50% of women after 48 hours. When given 24-48 hours before induction in women with IUFD, it reduces the induction to the delivery interval. There have been reports of neonatal antiglucocorticoid effects, as well as fetal renal and hepatic dysfunction when used with live fetuses, and its use is therefore restricted to women with IUFD. It is also used as the first of two medications given for medical termination of pregnancy which typically includes misoprostol as the second medication in different amounts and delivery methods depending upon the gestation age (43, 44).
Others
There are some additional pharmacological induction methods which have been used over time but not become the mainstay of therapy. For example, vaginal nitric oxide donors (e.g. isosorbide mononitrate or glyceryl trinitrate) are much slower than vaginal dinoprostone but carry lower rates of hyperstimulation. These methods commonly cause mild maternal side effects (headache in 90%), but maternal satisfaction is higher than for dinoprostone. Their gentle uterine effects may make them suitable for outpatient cervical ripening (45).
Oral corticosteroids, intracervical hyaluronidase injection, and oestrogens have all shown some effect, but there is not enough RCT evidence to comment on their safety and efficacy.